The nervous system exerts a powerful influence on control of blood pressure and other cardiovascular parameters. Most cardiovascular diseases, notably hypertension, involve pathogenic dysfunction of the autonomic nervous system. Angiotensin II (Ang ll) signaling in the central nervous system (CNS) has emerged as a primary culprit in driving neuro-cardiovascular dysfunction in hypertension, however the underlying molecular substrates and physiological circuits remain to be elucidated. Pioneering work a decade ago established that reactive oxygen species (ROS) play a pivotal role in hypertension caused by elevated circulating Ang ll. Since then, most investigations of Ang ll hypertension and ROS have focused on the vasculature or kidney. Funding during the previous cycle led to our discovery that redox signaling in CNS is critical in Ang ll-mediated neuro-cardiovascular regulation and disease. Building on this and implementing newly developed genetic tools for dissecting the functional role of oxidant molecules in the CNS, we will address the overall hypothesis that systemic Ang ll-dependent hypertension is caused by excessive production of specific NADPH oxidase (Nox)-derived ROS in key cardiovascular nuclei of the brain. Using a brain site-directed viral delivery system, we will introduce spatiotemporally controlled gene modifications for selective, localized and efficient modulation of the redox status of specific neural circuits in mouse brain. Coupled with sophisticated free radical biology and integrative cardiovascular physiology in conscious mice, we will dissect oxidant mechanisms of central neuro-cardiovascular control by addressing three hypotheses. 1) Systemic Ang ll-dependent hypertension and associated autonomic dysfunction are fueled by excessive generation of ROS in key cardiovascular nuclei of the brain. Causal links between abnormal central redox signaling and mechanisms underlying Ang ll-dependent neuro-cardiovascular deregulation will be investigated, with a focus on functionally mapping the physiological circuits and free radical species involved. 2) AT1a receptors in specific cardiovascular nuclei of the brain play a key role in excessive ROS production and central neuro-cardiovascular dysfunction caused by elevated systemic Ang ll levels. Two mouse models engineered for testing the role of brain AT1a receptors: one with expression of exogenous AT1a receptors selectively in CNS, and another with a floxed AT1a receptor gene for targeted Cre-mediated deletion will be used to dissect the role of redox signaling through central AT1a receptors in systemic Ang ll hypertension. 3) Specific Nox enzymes in key cardiovascular nuclei each play important and distinct roles in systemic Ang ll-induced hypertension and related neurohumoral sequelae. Expression patterns, regulation and neuro- cardiovascular function of Nox1, Nox2 and Nox3 in key CNS circuits will be investigated using viral delivery of specific Nox-targeted RNAi. This research has important implications for novel therapeutic use of CNS-directed antioxidants in humans with hypertension and other neuro-cardiovascular diseases.